U.S. patent number 9,989,544 [Application Number 14/795,285] was granted by the patent office on 2018-06-05 for sequence scheduling and sample distribution techniques.
This patent grant is currently assigned to ILLUMINA, INC.. The grantee listed for this patent is Illumina, Inc.. Invention is credited to Alexander G. Dickinson, Helmy A. Eltoukhy, Francisco Jose Garcia, Robert C. Kain, Min-Jui Richard Shen.
United States Patent |
9,989,544 |
Kain , et al. |
June 5, 2018 |
Sequence scheduling and sample distribution techniques
Abstract
A technique is disclosed for sample management for use in
conjunction with sequencing devices that sequence biological
samples, e.g., DNA and RNA. A sequencing device or a network of
sequencing devices may be scheduled according to the
characteristics of the samples in queue and the capabilities and
availability of sequencing devices. Biological samples may be
automatically queued and loaded via a sample distribution system. A
sample distribution system may be used to reduce operator
intervention.
Inventors: |
Kain; Robert C. (San Diego,
CA), Dickinson; Alexander G. (Laguna Beach, CA), Shen;
Min-Jui Richard (Poway, CA), Eltoukhy; Helmy A.
(Woodside, CA), Garcia; Francisco Jose (San Diego, CA) |
Applicant: |
Name |
City |
State |
Country |
Type |
Illumina, Inc. |
San Diego |
CA |
US |
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Assignee: |
ILLUMINA, INC. (San Diego,
CA)
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Family
ID: |
50622717 |
Appl.
No.: |
14/795,285 |
Filed: |
July 9, 2015 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20150309058 A1 |
Oct 29, 2015 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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13668686 |
Nov 5, 2012 |
9116139 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
B01J
19/00 (20130101); G01N 35/0092 (20130101); G01N
35/00871 (20130101) |
Current International
Class: |
G01N
35/00 (20060101); B01J 19/00 (20060101) |
Field of
Search: |
;700/266
;702/19,20,22,31,32 ;930/10 ;506/43 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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Jul 2005 |
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WO |
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2006064199 |
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Jun 2006 |
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WO |
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2007010251 |
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Jan 2007 |
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WO |
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2011067559 |
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Jun 2011 |
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WO |
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Other References
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Operations Manual Version 4.0 (1999). cited by applicant .
Marra et al., High-throughput plasmid DNA purification for 3 cents
per sample, Nucleic Acids Research, 1999, vol. 27, No. 24. cited by
applicant .
Margulies et al., Genome sequencing in microfabricated high-density
picolitre reactors, Nature, vol. 437, Sep. 15,
2005/doi:10.1038/nature03959. cited by applicant .
Bentley et al., Accurate whole human genome sequencing using
reversible terminator chemistry, vol. 456, Nov. 6,
2008/doi:10.1038/nature07517. cited by applicant .
Lundquist et al. "Parallel confocal detection of single molecules
in real time", Opt. Lett. 33, 1026-1028 (2008). cited by applicant
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Levene et al. "Zero-Mode Waveguides for Single-Molecule Analysis at
High Concentrations", Science 299, 682-686 (2003). cited by
applicant .
Cockroft, et al. "A Single-Molecule Nanoprene Device Detects DNA
Polymerase Activity with Single-Nucleotide Resolution", J. Am.
Chem. Soc. 130, 818-820 (2008). cited by applicant .
Healy, "Nanopore-based single-molecule DNA analysis", Nanomed. 2,
459-481 (2007). cited by applicant .
Soni & Meller, "Progress toward Ultrafast DNA Sequencing Using
Solid-State Nanopores", Clin. Chem. 53, 1996-2001 (2007). cited by
applicant .
Korlach et al. "Selective aluminum passivation for targeted
immobilization of single DNA polymerase molecules in zero-mode
waveguide nanostructures", Proc. Natl. Acad. Sci. USA 105,
1176-1181 (2008). cited by applicant .
Bentley et al., Supplemental Information, www.nature.com,
doi:10.10381 nature07517(2008). cited by applicant.
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Primary Examiner: Sasaki; Shogo
Attorney, Agent or Firm: Fletcher Yoder PC
Parent Case Text
CROSS REFERENCE TO RELATED APPLICATION
This application is a continuation of U.S. patent application Ser.
No. 13/668,686, now U.S. Pat. No. 9,116,139, entitled "Sequence
Scheduling and Sample Distribution Techniques," filed Nov. 5, 2012,
which is herein incorporated in its entirety by reference.
Claims
The invention claimed is:
1. A computer system for assigning sequencing runs for biological
samples, comprising: a plurality of sequencing devices respectively
configured to acquire sequence data indicative of nucleotide
identities from a respective plurality of biological samples during
a sequencing run and communicate information related to an
availability to sequence at least one of the plurality of
biological samples; a memory circuit including executable
application instructions stored therein; and a processor configured
to execute the application instructions stored in the memory
circuit, wherein the application instructions comprise instructions
for: receiving information related to the availability of the
plurality of sequencing devices; receiving identification
information for the plurality of biological samples, wherein the
identification information comprises sample preparation information
for each respective biological sample of the plurality of
biological samples; identifying a subset of the plurality of
sequencing devices that have a sample preparation compatibility
with an individual biological sample of the plurality of biological
samples based on the sample preparation information; assigning the
individual biological sample to an individual sequencing device of
the subset based at least in part on the information related to the
availability and the sample preparation compatibility of each
respective sequencing device of the plurality of sequencing
devices; and providing an indication that the individual sequencing
device is available to sequence the individual biological sample
based on the information related to the availability and the sample
preparation compatibility.
2. The system of claim 1, wherein, when the individual biological
sample of the plurality of biological samples has a high priority
designation and no sequencing device is available, the application
instructions comprise providing an override indication and
assigning the individual biological sample to the individual
sequencing device based on a determination that a sufficient
percentage of sequence data has been acquired of an ongoing
incomplete sequencing run.
3. The system of claim 1, wherein, when the individual biological
sample of the plurality of biological samples has a high priority
designation and no sequencing device is available, the application
instructions comprise assigning the individual biological sample to
the sequencing device based on a surface sample density of an
ongoing sequencing run and providing an indication to add the
individual biological sample to the ongoing sequencing run.
4. The system of claim 3, wherein the application instructions
comprise providing an indication that the individual biological
sample should be tagged to distinguish the biological sample from
the ongoing sequencing run.
5. The system of claim 1, wherein the application instructions
comprise determining an earliest possible availability for an
unavailable sequencing device by determining of a percentage of
sufficient completion of an ongoing incomplete sequencing run.
6. The system of claim 1, wherein the application instructions
comprise assigning each of the plurality of biological samples to
respective sequencing devices based at least in part on an
estimated total processing load of the plurality of sequencing
devices.
7. The system of claim 6, wherein the assigning comprises smoothing
the processing load over a period of time.
8. The system of claim 6, wherein the assigning comprises
increasing the processing load at particular times.
9. The system of claim 6, wherein the assigning comprises
determining if the sequencing device is capable of performing
analysis in the cloud.
10. The system of claim 1, wherein the application instructions
comprise instructions for receiving information related to
sequencing capabilities of the plurality of sequencing devices,
wherein the sequencing capabilities relate to capabilities of
operating according to one or more sequencing protocols.
11. The system of claim 10, wherein the instructions for assigning
the individual biological sample to the individual sequencing
device comprise determining a compatibility between a desired
nucleotide sequencing assay type for the individual biological
sample and the sequencing capabilities of the individual sequencing
device.
12. The system of claim 1, wherein the application instructions
comprise providing instructions to a sample loading system to load
the individual biological sample into the assigned individual
sequencing device when the assigned individual sequencing device is
available.
13. The system of claim 1, wherein the memory circuit and the
processor are disposed on one of the plurality of sequencing
devices.
14. The system of claim 1, wherein the subset comprises sequencing
devices of the plurality of sequencing devices from a particular
manufacturer.
15. The system of claim 1, wherein the sample preparation
information comprises sample tag information, and wherein the
subset comprises sequencing devices of the plurality of sequencing
devices configured to sequence multiple biological samples
simultaneously when at least one of the multiple biological samples
comprises the sample tag.
16. The system of claim 1, wherein the individual sequencing device
is configured to simultaneously sequence a predetermined number of
biological samples prepared according to a same sample preparation
protocol subset.
17. The system of claim 1, wherein the individual sequencing device
is available when the predetermined number of biological samples
has not yet been loaded onto the individual sequencing device.
18. The system of claim 1, wherein the application instructions
comprise instructions for identifying the subset of the plurality
of sequencing devices further based on a compatibility between
sequencing parameter information of the individual biological
sample and sequencing capabilities of the plurality of sequencing
devices.
19. The system of claim 1, wherein the application instructions
comprise instructions for interrupting an ongoing sequencing run of
the individual biological sample based on a presence of a
homopolymer region of interest in the sequence data.
20. The system of claim 19, wherein the application instructions
comprise instructions for reassigning the individual biological
sample to another sequencing device of the subset after the
interrupting based on the presence of a homopolymer region of
interest in the sequence data.
21. The system of claim 1, wherein the application instructions
comprise instructions for reassigning the individual biological
sample to another sequencing device of the plurality of sequencing
devices based on an analysis of the sequence data of other
biological samples of the plurality of biological samples.
Description
BACKGROUND
The present disclosure relates generally to the field of genetic
sequencing. More particularly, the disclosure relates to improved
techniques for throughput of automating sequencing of genetic
materials by use of automated scheduling and/or automated sample
distribution.
Genetic sequencing has become an increasingly important area of
genetic research, promising future uses in diagnostic and other
applications. In general, genetic sequencing consists of
determining the order of nucleotides for a nucleic acid such as a
fragment of RNA or DNA. Relatively short sequences are typically
analyzed, and the resulting sequence information may be used in
various bioinformatics methods to align fragments against a
reference sequence or to logically fit fragments together so as to
reliably determine the sequence of much more extensive lengths of
genetic material from which the fragments were derived. Automated,
computer-based examination of characteristic fragments have been
developed, and have been used more recently in genome mapping,
analysis of genetic variation between individuals, identification
of genes and their function, and so forth. However, existing
techniques are highly time-intensive, and resulting genomic
information is accordingly extremely costly.
A number of alternative sequencing techniques are presently under
investigation and development. These include the use of microarrays
of genetic material that can be manipulated so as to permit
parallel detection of the ordering of nucleotides in a multitude of
fragments of genetic material. The arrays typically include many
sites formed or disposed on a substrate. Additional materials,
typically single nucleotides or strands of nucleotides
(oligonucleotides), are introduced and permitted or encouraged to
bind to the template of genetic material to be sequenced, thereby
selectively marking the template in a sequence dependent manner.
Sequence information may then be gathered by imaging the sites. In
certain current techniques, for example, each nucleotide type is
tagged with a fluorescent tag or dye that permits analysis of the
nucleotide attached at a particular site to be determined by
analysis of image data.
Although such techniques show promise for significantly improving
throughput and reducing the cost of sequencing, further progress in
the parallelization, speed and reliability of sequencing is
desirable.
BRIEF DESCRIPTION
The present disclosure provides significant improvements in the
field of nucleic acid sequencing, especially with regard to
biological sample management methods. The techniques may be used
for high throughput sequencing, and will typically be most useful
in sequencing of DNA and RNA (including cDNA). However, the
biological sample distribution and/or scheduling techniques may be
used for any suitable type of sample analysis devices. In certain
embodiments, the techniques may be used with a variety of
sequencing approaches or technologies, including techniques often
referred to as sequencing-by-synthesis (SBS),
sequencing-by-ligation, pyrosequencing, nanopore sequencing and so
forth. The present techniques have been found or are believed to
provide for more highly automated or higher quality sequencing,
permitting higher throughput and ultimately reduced sequence costs
by providing improved scheduling and decreased downtime for
sequencing devices. Further, the techniques facilitate improved
sample loading or queuing.
In one embodiment, the present disclosure provides a novel approach
for scheduling sequencing runs for a group or network of sequencing
devices. For example, such a group or network may be located in a
high throughput sequencing lab or a core sequencing facility.
Sequencing devices represent large capital investments, and
optimized scheduling of sequencing runs (e.g., sample processing,
data collection, and/or analysis) avoids idle time on a sequencer
and loss of resources. The techniques relate to a controller or
processor-based device that assigns biological samples to
sequencing devices based on parameters associated with the sample
(e.g., type of assay to be performed, a priority designation) and
parameters associated with the sequencing device (e.g., estimated
availability, sequencing capabilities). The processor-based device
accesses the relevant data and creates a sequencing schedule,
including sample assignments to particular devices. The sequencing
schedule is dynamic and changes according to the new information
from newly added samples in the queue. For example, a higher
priority sample may jump in the line over a lower priority sample.
In particular embodiments, the sequencing schedule may include an
assessment of in-progress sequencing. Certain sequencing runs may
have collected sufficient data to assemble a sequence even if the
sequencing run is not yet complete. In one example, such runs may
be interrupted and the associated sequencing device reassigned to
another biological sample to optimize use of the sequencing device.
In another example, a sequencing device that is underutilized may
be assigned another biological sample to be loaded into an
in-progress run that is not interrupted for the new sample.
Instead, the new sample is sequenced together with the in-progress
sample. In a third example, the priority of a sample in a queue may
be raised or lowered based on sequencing data obtained on a
sequencing device in the network or group of devices. In such
cases, two or more samples may be related and the results from a
first sample may indicate that analysis of a second, related sample
should be carried out on a more expedited basis that previously
determined (or conversely on a lower priority basis than a third
sample).
The present techniques also involve networked or distributed
control of a plurality of sequencing devices to optimize the
performance of the network as a whole. In certain embodiments, the
network may be a star-type arrangement with a central controller.
In other embodiments, the network may be a ring-type arrangement in
which the controller resides on one or more of the networked
sequencing devices. Regardless of the particular arrangement, the
sequencing devices may be controlled or scheduled such that
particular devices are in use at particular times with the goal of
adjusting the processing load of the network. In one embodiment,
the controller arbitrates between local processing and cloud-based
processing of the sequencing data based on an estimated processing
load for the network.
In another embodiment, the present techniques include a sample
distribution system that is configured to facilitate sample loading
into one or more sequencing devices. As opposed to techniques in
which biological samples are loaded by hand into a device, the
sample distribution system may provide automatic loading from a
central sample station and under processor-based control. Further,
the sample distribution system may be implemented as a
plug-and-play arrangement that works with a variety of sequencing
devices. In one embodiment, the sample distribution system is
provided as a backplane arrangement that works in conjunction with
a sequencing device rack. The sample distribution system may be
integrated with the sequencing scheduling techniques as provided
herein. That is, the instructions for loading the samples may be
provided by the sequencing scheduling system. In other embodiments,
the sample distribution system may be provided as a standalone
system with a user interface to provide loading instructions.
The present disclosure provides a system for scheduling sequencing
runs for a plurality of biological samples. The system includes a
memory circuit including executable application instructions and a
processor configured to execute the application instructions. The
processor is configured to execute instructions for receiving
information related to availability of the plurality of sequencing
devices; receiving identification information for a plurality of
biological samples, wherein the identification information
comprises sequencing parameters and a priority designation;
assigning each of the plurality of biological samples to respective
sequencing devices based at least in part on the availability of
each respective sequencing device and the sequencing parameters and
the priority designation of each respective sample; and providing
an indication that one of the plurality of biological samples is
ready to be sequenced based on an availability of an assigned
sequencing device.
The present disclosure also provides a sequencing device that
includes a module configured to acquire digitized signal data from
a first biological sample during a sequencing run. The sequencing
device also includes at least one processor configured to: receive
the digitized signal data; determine nucleotide identities of the
first biological sample based on the digitized signal data; output
one or more files comprising the nucleotide identities; analyze the
nucleotide identities to determine if enough digitized signal data
has been acquired from the first biological sample; communicate
that the sequencing device is available when enough digitized
signal data has been acquired from the first biological sample
while the module is acquiring additional digitized signal data from
the first biological sample; and receive an indication that the
sequencing run will be interrupted and the sequencing reassigned to
a second biological sample when the sequencing device is
available.
The present disclosure also provides a sample distribution system.
The sample distribution system includes a sample rack for storing a
plurality of individual biological samples; a plurality of conduits
configured to couple to each respective biological sample and to
transfer each respective biological sample within the system; a
sample inlet path in fluid communication with a sample loading port
of a biological analysis device; a valve that controls fluid
communication between the plurality of conduits and the sample
inlet path such that only one conduit of the plurality of conduits
is in communication with the sample inlet path at a given time and
such that the biological sample coupled to the only one conduit is
in fluid communication with the sample loading port via the sample
inlet path; and a controller coupled to the valve and configured to
receive instructions to load a biological sample into the
biological analysis device and open a fluid communication pathway
between a conduit coupled to the biological sample and the sample
loading port.
The present disclosure also includes a sequencing network. The
sequencing network includes a plurality of sequencing devices
configured to acquire digitized signal data from a biological
sample during a sequencing run and communicate information about
the sequencing run. The sequencing network also includes a
controller coupled to the plurality of sequencing devices, wherein
the controller comprises: a memory circuit including executable
application instructions stored therein; and a processor configured
to execute the application instructions stored in the memory
device, wherein the application instruction comprise instructions
for: receiving the information related to sequencing run for each
respective sequencing device; receiving identification information
for a plurality of biological samples, wherein the identification
information comprises sequencing parameters and a priority
designation; and assigning each of the plurality of biological
samples to respective sequencing devices based at least in part on
the information related to sequencing run of each respective
sequencing device and the sequencing parameters and the priority
designation of each respective sample.
The present disclosure provides a system for scheduling sequencing
runs for a plurality of biological samples. The system includes a
memory circuit including executable application instructions stored
therein; and a processor configured to execute the application
instructions stored in the memory device, wherein the application
instructions comprise instructions for: receiving information
related to sequencing capability of the plurality of sequencing
devices; receiving identification information for a plurality of
biological samples, wherein the identification information
comprises sequencing parameters and a priority designation;
assigning each of the plurality of biological samples to respective
sequencing devices based at least in part on the sequencing
capability of each respective sequencing device and the sequencing
parameters and the priority designation of each respective sample;
and providing an indication that one of the plurality of biological
samples is ready to be sequenced based on an a sequencing
capability of an assigned sequencing device.
Embodiments of the present techniques are described herein by
reference to biological samples for a sequencing device. The
disclosure is not, however, limited by the advantages of the
aforementioned embodiment. The present techniques may also be
applied to devices capable of generating other types of high
throughput biological data, such as microarray data or library
screening data (e.g. from screening candidate drugs or from
screening engineered protein variants).
DRAWINGS
These and other features, aspects, and advantages of the present
invention will become better understood when the following detailed
description is read with reference to the accompanying drawings in
which like characters represent like parts throughout the drawings,
wherein:
FIG. 1 is a diagrammatical overview of a sequencing system
incorporating aspects of the present technique;
FIG. 2 is a diagrammatical overview of a sequencing device that may
be used in conjunction with the system of the type discussed with
reference to FIG. 1;
FIG. 3 is a perspective view of a sequencing device including a
sample cartridge that may be used in conjunction with the system of
the type discussed with reference to FIG. 1;
FIG. 4 is a flow diagram of a method of interaction between a
sequencing device and a scheduling controller that may be performed
in conjunction with the system discussed with reference to FIG.
1;
FIG. 5 is a flow diagram of a method of interaction between a
plurality of sequencing devices and a scheduling controller that
may be performed in conjunction with the system discussed with
reference to FIG. 1;
FIG. 6 is a flow diagram of a method of generating a sequencing
sample schedule that may be performed in conjunction with the
system discussed with reference to FIG. 1;
FIG. 7 is a flow diagram of a method of generating a sequencing
sample schedule that may be performed in conjunction with the
system discussed with reference to FIG. 1;
FIG. 8 is a flow diagram of a method of distributing sample
analysis that may be performed in conjunction with the system
discussed with reference to FIG. 1;
FIG. 9 is a diagrammatical overview of a sample distribution system
incorporating aspects of the present technique;
FIG. 10 is a diagrammatical overview of a sample distribution
system including a rack-based sequencing system incorporating
aspects of the present technique; and
FIG. 11 is a perspective view of a plug-and-play backplane that may
be used in conjunction with the system discussed with reference to
FIG. 9.
DETAILED DESCRIPTION
The following detailed description of certain embodiments will be
better understood when read in conjunction with the appended
drawings. To the extent that the figures illustrate diagrams of the
functional blocks of various embodiments, the functional blocks are
not necessarily indicative of the division between hardware
circuitry. Thus, for example, one or more of the functional blocks
(e.g., processors or memories) may be implemented in a single piece
of hardware (e.g., a general purpose signal processor or random
access memory, hard disk, or the like). Similarly, the programs may
be stand alone programs, may be incorporated as subroutines in an
operating system, may be functions in an installed software
package, and the like. It should be understood that the various
embodiments are not limited to the arrangements and instrumentality
shown in the drawings.
Embodiments described herein may be used in various biological or
chemical processes and systems for academic or commercial analysis.
More specifically, embodiments described herein may be used in
various processes and systems where it is desired to detect an
event, property, quality, or characteristic that is indicative of a
desired reaction.
As used herein, an element or step recited in the singular and
proceeded with the word "a" or "an" should be understood as not
excluding plural of said elements or steps, unless such exclusion
is explicitly stated. Furthermore, references to "one embodiment"
are not intended to be interpreted as excluding the existence of
additional embodiments that also incorporate the recited features.
Moreover, unless explicitly stated to the contrary, embodiments
"comprising" or "having" an element or a plurality of elements
having a particular property may include additional elements
whether or not they have that property.
Turning now to the drawings, and referring first to FIG. 1, a
management system 10 for biological sample scheduling is
illustrated diagrammatically. The system 10 includes one or more
controllers 12 coupled to one or more sequencing devices 16 via
suitable communications links 18. The system 10 also includes an
input for information related to samples 20 via communication link
22. For example, each individual sample 20 may include a barcode or
RFID tag that communicates with the scheduling controller 12. The
communication may occur via any suitable arrangement and protocol,
such as via a local area network (LAN), a general wide area network
(WAN), and/or a public network (e.g., the Internet) via the
communications links 18 and 24. In other embodiments, some or all
of the received data may be entered by a user, including sample
identification information. That is, the system 10 can be
configured to receive data and information from various devices,
including users of devices for generating biological data. Such
data may be used to assess the availability and/or capabilities of
the associated sequencing devices 16 to generate a sequencing
schedule for samples that need to be analyzed. The data may also be
used to generate a priority designation for the samples waiting to
be analyzed. As additional samples join the queue, the system is
capable of receiving additional information to create a dynamic
schedule that may rearrange the proposed sequencing times if higher
priority samples join the queue.
In embodiments in which there are multiple sequencing devices 16,
the controller arrangement may be a star arrangement in which the
sequencing devices 16 all communicate with a central controller 12.
Other arrangements may include ring-based arrangement in which the
controller 12 resides on or is associated with one or more
sequencing devices 16. That is, the functionality of the controller
12 may be incorporated into the sequencing device 16. Further, the
sequencing devices 16 may communicate with one another to
distribute computing resources.
The scheduling controller 12 may be implemented as one or more of a
personal computer system, server computer system, thin client,
thick client, hand-held or laptop device, multiprocessor system,
microprocessor-based system, set top box, programmable consumer
electronic, network PC, minicomputer system, smart phone (e.g.
iPhone), tablet computer (e.g. iPad), mainframe computer system,
and distributed cloud computing environments that include any of
the above systems or devices, and the like. The scheduling
controller 12 may include one or more processors or processing
units 28, a memory architecture 32 that may include RAM 34 and
non-volatile memory 36. The memory architecture 32 may further
include removable/non-removable, volatile/non-volatile computer
system storage media. Further, the memory architecture 32 may
include one or more readers for reading from and writing to a
non-removable, non-volatile magnetic media, such as a hard drive, a
magnetic disk drive for reading from and writing to a removable,
non-volatile magnetic disk (e.g., a "floppy disk"), and/or an
optical disk drive for reading from or writing to a removable,
non-volatile optical disk such as a CD-ROM, DVD-ROM. The controller
12 may also include a variety of computer system readable media.
Such media may be any available media that is accessible by the
cloud computing environment, such as volatile and non-volatile
media, and removable and non-removable media.
The memory architecture 32 may include at least one program product
having a set (e.g., at least one) of program modules implemented as
executable instructions that are configured to carry out the
functions of the present techniques. For example, executable
instructions 38 may include an operating system, one or more
application programs, other program modules, and program data.
Generally, program modules may include routines, programs, objects,
components, logic, data structures, and so on, that perform
particular tasks or implement particular abstract data types.
Program modules may carry out the functions and/or methodologies of
the techniques as described herein including, but not limited to,
scheduling management and/or sample distribution.
The components of the controller 12 may be coupled by an internal
bus 39 that may be implemented as one or more of any of several
types of bus structures, including a memory bus or memory
controller, a peripheral bus, an accelerated graphics port, and a
processor or local bus using any of a variety of bus architectures.
By way of example, and not limitation, such architectures include
Industry Standard Architecture (ISA) bus, Micro Channel
Architecture (MCA) bus, Enhanced ISA (EISA) bus, Video Electronics
Standards Association (VESA) local bus, and Peripheral Component
Interconnects (PCI) bus.
The controller may also communicate with one or more external
devices such as a keyboard, a pointing device, a display 42, etc.;
that enable a user to interact with the controller 12; and/or any
devices (e.g., network card, modem, etc.) that enable the
controller 12 to communicate with one or more other computing
devices. Such communication can occur via I/O interfaces 44. Still
yet, the controller 12 may communicate with one or more networks
such as a local area network (LAN), a general wide area network
(WAN), a public network (e.g., the Internet), and/or a cloud
computing environment via a suitable network adapter.
As provided herein, the system 10 is configured to be used in
conjunction with one or more devices that analyze biological
samples 20. The system 10 provides a schedule for biological
samples 20 to be loaded into individual devices. The system 10 may
generate a proposed schedule in which waiting samples 20 are
assigned an estimated sequencing time (e.g., a time to be loaded)
and are assigned to a particular device. In this manner, an
operator may consult the generated schedule before loading samples
20 into the sequencing devices 16. The system 10 may also generate
alarms or other indications to an operator. For example, when a
scheduled sample 20 is ready to be loaded into an individual
sequencing device 16, the system 10 may provide an alarm or other
indication to an operator. In one embodiment, the system 10 may
send a text message to a pager or mobile device indicating that a
sample 20 is ready to be loaded. The system 10 may also acknowledge
that a particular sample 20 has been loaded and update the schedule
accordingly. In one embodiment, the sample 20 is scanned before
being loaded and the sample information is stored by the controller
12. In another embodiment, an operator may confirm that the sample
20 has been loaded. Although embodiments of the present disclosure
are depicted in conjunction with sequencing devices, it should be
understood that, in certain embodiments, the present techniques may
be used in conjunction with other types of devices. Further, the
present techniques may also be used in conjunction with an
automatic sample distribution system. In such embodiments, the
samples 20 are loaded without operator intervention.
The controller 12 may provide a user interface that guides an
operator through a series of setup options. For example, upon
receiving a sample 20, the operator may specify information about
the sample 20 (desired assay types, priority information, sample
preparation information, patient information, organism, date or
time of sample collection, location of sample collection,
circumstances of sample collection, suspected sample
characteristics, etc.) and may select from available sequencing
devices that may be appropriate. Accordingly, even though the
controller 12 may be configured to match the sample 20 to the
sequencing device 16 according to a rules-based protocol, the
operator may also add conditions or parameters that override the
protocol. For example, the sample 20 may be prepared according to a
kit that is optimized for use with sequencing devices from a
particular manufacturer. In such an embodiment, the operator may
specify the sample 20 should be matched to sequencing devices 16
from that manufacturer. In other embodiments, the user interface
may provide menu options that prompt user input with regard to
particular sample preparation kits or tagging and use the
information in the matching protocol.
FIG. 2 is a schematic diagram of the sequencing device 16 that may
be used in conjunction with the system 10. The sequence device 16
may be implemented according to any sequencing technique, such as
those incorporating sequencing-by-synthesis methods described in
U.S. Patent Publication Nos. 2007/0166705; 2006/0188901;
2006/0240439; 2006/0281109; 2005/0100900; U.S. Pat. No. 7,057,026;
WO 05/065814; WO 06/064199; WO 07/010,251, the disclosures of which
are incorporated herein by reference in their entireties.
Alternatively, sequencing by ligation techniques may be used in the
sequencing device 16. Such techniques use DNA ligase to incorporate
oligonucleotides and identify the incorporation of such
oligonucleotides and are described in U.S. Pat. No. 6,969,488; U.S.
Pat. No. 6,172,218; and U.S. Pat. No. 6,306,597; the disclosures of
which are incorporated herein by reference in their entireties.
Some embodiments can utilize nanopore sequencing, whereby target
nucleic acid strands, or nucleotides exonucleolytically removed
from target nucleic acids, pass through a nanopore. As the target
nucleic acids or nucleotides pass through the nanopore, each type
of base can be identified, for example, by measuring fluctuations
in the electrical conductance of the pore (U.S. Pat. No. 7,001,792;
Soni & Meller, Clin. Chem. 53, 1996-2001 (2007); Healy,
Nanomed. 2, 459-481 (2007); and Cockroft, et al. J. Am. Chem. Soc.
130, 818-820 (2008), the disclosures of which are incorporated
herein by reference in their entireties). Yet other embodiments
include detection of a proton released upon incorporation of a
nucleotide into an extension product. For example, sequencing based
on detection of released protons can use an electrical detector and
associated techniques that are commercially available from Ion
Torrent (Guilford, Conn., a Life Technologies subsidiary) or
sequencing methods and systems described in US 2009/0026082 A1; US
2009/0127589 A1; US 2010/0137143 A1; or US 2010/0282617 A1, each of
which is incorporated herein by reference in its entirety.
Particular embodiments can utilize methods involving the real-time
monitoring of DNA polymerase activity. Nucleotide incorporations
can be detected through fluorescence resonance energy transfer
(FRET) interactions between a fluorophore-bearing polymerase and
.gamma.-phosphate-labeled nucleotides, or with zeromode waveguides
as described, for example, in Levene et al. Science 299, 682-686
(2003); Lundquist et al. Opt. Lett. 33, 1026-1028 (2008); Korlach
et al. Proc. Natl. Acad. Sci. USA 105, 1176-1181 (2008), the
disclosures of which are incorporated herein by reference in their
entireties. Other suitable alternative techniques include, for
example, fluorescent in situ sequencing (FISSEQ), and Massively
Parallel Signature Sequencing (MPSS). In particular embodiments,
the sequencing device 16 may be a HiSeq, MiSeq, or HiScanSQ from
Illumina (San Diego, Calif.).
Different types of sequencing devices can provide different
advantages and disadvantages. For example, different sequencing
devices vary in raw read length (e.g. length of contiguous
nucleotide positions that are determined for a given nucleic acid
fragment in a single instrument run), raw read accuracy (e.g.
probability of an error occurring in the read of a particular
nucleic acid fragment), depth of sequencing provided per run (e.g.
number of nucleic acid fragments read in a run), accuracy in
determining the length of homopolymeric regions, and accuracy in
reading sequence regions having particular compositions (e.g. GC
rich regions vs. AT rich regions). An advantage of having a variety
of types of sequencing devices in a network or group of sequencing
devices is that a particular device can be selected to suit a
desired inquiry. For example, in an application where overall
accuracy is of paramount importance it may be desirable to select a
sequencer that provides a high depth of sequencing (which results
in increased accuracy after data analysis) even if this means using
a device that has shorter overall read length. Alternatively, for
de novo genome sequencing applications it may be more desirable to
select a sequencer that generates longer read lengths even if the
selected device is not the most accurate in the network. Of course
a particular sample can be sequenced on multiple types of
sequencing devices to obtain the combined benefits of more than one
device.
In accordance with the systems and methods set forth herein,
particular samples can be prioritized for use on a certain type of
sequencer based on sample characteristics, data quality (or
quantity) expectations etc. A change can be made in this priority
for a particular sample in a queue based on data obtained for a
related or similar sample. For example, several related samples can
be initially slated for sequencing on a first device that generates
longer read lengths than a second device but that is not as
accurate at determining homopolymer lengths as the second device.
In the event that sequencing of one of the samples indicates the
presence of homopolymer regions of interest, the priority of the
related samples in the queue can be changed to shunt them to the
second sequencing device where more accurate reads of homopolymer
regions can be obtained. Similarly, several related samples can be
initially prioritized for evaluation using a particular protocol
(which, in certain embodiments, may include preset, user modified,
or custom protocols), and the priority for samples in the queue for
that protocol can be modified based on results obtained for one of
the samples. For example, samples that were initially designated
for a relatively time consuming, deep sequencing protocol can be
re-designated for a lower depth and faster protocol if the results
from a first sample indicate an urgent need to get preliminary
data. Such a situation can arise for example, if it becomes
apparent from sequencing data that the first sample contained a
fast acting pathogen that should be rapidly diagnosed in the other
samples. In one example, a sequencing run may determine is a sample
is positive for salmonella DNA. The runs may proceed until
identification is possible.
In one embodiment, the sample priority may be based on a desired
error rate. That is, certain samples may have a wider tolerance of
acceptable error rates (depending on the end use of the sequencing
data), and may be scheduled on a wider array of assays and/or
devices relative to a sample with more stringent or lower error
rate specifications (e.g., forensic samples). For example, an
estimated potential error rate may be related to the number of
reads and/or the length of the reads as well as the number of
cycles. In another embodiment, a run may be continued until a
determination is made that an error rate is too high for adequate
data analysis.
The disclosed techniques may also incorporate scheduling or
assignment information for other types of analysis devices or
orthogonal techniques (purification, chromatography, SNP analysis,
etc, antibody or PCR-based techniques). Further, the sequencing
runs may be followed by a recommended or independent validation
step
In the depicted embodiment, the sequencing device 16 includes a
separate sample processing device 50 and an associated computer 52.
However, these may be implemented as a single device. Further, the
associated computer 52 may be local to or networked with the sample
processing device 50. The devices may include identification
components, such as barcodes or RFID tags, that facilitate
identification of users, samples, and/or devices. In other
embodiments, the computer 52 may be capable of communicating with a
cloud computing environment that is remote from the sequencing
device 16. That is, the computer 52 may be capable of communicating
with the sequencing device 16 through the cloud computing
environment. In the depicted embodiment, the biological sample may
be loaded into the sample processing device 50 as a sample slide 70
that is detected to generate sequence data. For example, reagents
that interact with the biological sample may fluoresce at
particular wavelengths in response to an excitation beam generated
by a detection module 72 and thereby return radiation for imaging.
For instance, the fluorescent components may be generated by
fluorescently tagged nucleic acids that hybridize to complementary
molecules of the components or to fluorescently tagged nucleotides
that are incorporated into an oligonucleotide using a polymerase.
As will be appreciated by those skilled in the art, the wavelength
at which the dyes of the sample are excited and the wavelength at
which they fluoresce will depend upon the absorption and emission
spectra of the specific dyes. Such returned radiation may propagate
back through the directing optics. This retrobeam may generally be
directed toward detection optics of the detection module 72.
Although the system of FIG. 2 is exemplified in regard to an
optical imaging detector, it will be understood that other
detectors can be used. The detection module can be physically
separated from the sample slide, for example via an optical train
used in many imaging devices. Alternatively, the detection module
can be integrated with the slide (or other sample carrier), for
example, as is the case for nanopore sequencing devices and
CMOS-based proton detection devices set forth previously herein
including in the incorporated references.
Taking the example of optical detection systems, the imaging module
detection optics may be based upon any suitable technology, and may
be, for example, a charged coupled device (CCD) sensor that
generates pixilated image data based upon photons impacting
locations in the device. However, it will be understood that any of
a variety of other detectors may also be used including, but not
limited to, a detector array configured for time delay integration
(TDI) operation, a complementary metal oxide semiconductor (CMOS)
detector, an avalanche photodiode (APD) detector, a Geiger-mode
photon counter, or any other suitable detector. TDI mode detection
can be coupled with line scanning as described in U.S. Pat. No.
7,329,860, which is incorporated herein by reference. Other useful
detectors are described, for example, in the references provided
previously herein in the context of various nucleic acid sequencing
methodologies.
The detection module 72 may be under processor control, e.g., via a
processor 74, and the sample receiving device 18 may also include
I/O controls 76, an internal bus 78, non-volatile memory 80, RAM 82
and any other memory structure such that the memory is capable of
storing executable instructions, and other suitable hardware
components that may be similar to those described with regard to
FIG. 2. Further, the associated computer 20 may also include a
processor 84, I/O controls 86, a communications module 87, and a
memory architecture including RAM 88 and non-volatile memory 90,
such that the memory architecture is capable of storing executable
instructions 92. The hardware components may be linked by an
internal bus 94, which may also link to the display 96. In
embodiments in which the sequencing device 16 is implemented as an
all-in-one device, certain redundant hardware elements may be
eliminated. Further, the sequencing device 16 may also interact
with the cloud computing environment. Such embodiments may be
beneficial for distributing processing load for the system 10.
The system 10 may include multiple sequencing devices 16, each with
the same or different capabilities. That is, the sequencing devices
16 may be capable of performing different types of assays or
sequencing runs, including DNA sequencing, RNA sequencing,
genotyping, SNP testing, CNV analysis, methylation analysis, gene
expression analysis, agrigenomics, cytogenetics, and/or cancer
genomics. Further, devices with similar assay capabilities (e.g.,
DNA sequencing) may perform at different speeds, with different
resolution, and with different sample preparation specifications.
The system 10 may be capable of tracking such differences to assign
the sample 20 to the appropriate sequencing device 16. In
particular embodiments, the devices 16 may operate with a cartridge
system that allows the devices to switch assay capabilities via the
changing out of internal cartridges. Certain other components are
associated with a device housing and are interoperable with a
variety of cartridges. In this manner, each device 16, when
available, may offer a range of assay capabilities depending on the
characteristics of the inserted cartridge.
FIG. 3 shows an exemplary sequencing device 16 that incorporates a
cartridge 100 that is configured to be inserted into a housing 102.
The cartridge 100 exploits advantages of integrated optoelectronics
and cartridge-based fluidics that are provided by several
embodiments set forth herein. The housing 102 contains various
fixed components including, for example, optical components,
computational components, power source, fan and the like. A screen
103 present, for example, on the front face of the housing 102
functions as a graphical user interface that can provide various
types of information such as operational status, status of an
analytical procedure (e.g. a sequencing run) being carried out,
status of data transfer to or from the device 16, instructions for
use, warnings or the like. A cartridge receptacle 104 is also
present on the front face of the housing 102. As shown, the
cartridge receptacle 104 can be configured as a slot having a
protective door 105. A status indicator 106, in the form of an
indicator light on the frame of the cartridge receptacle in this
example, is present and can be configured to indicate the presence
or absence of a cartridge in the device 16. For example the
indicator light 106 can change from on to off or from one color to
another to indicate presence or absence of a cartridge. A power
control button 107 is present on the front face of the housing 102
in this example as is identifying indicia 108 such as the name of
the manufacturer or instrument. In particular embodiments, the
cartridge 100 may include an identification element that
communicates via handshake with the housing 102 to confirm that the
cartridge is compatible with the processing elements available in
the housing 102.
The cartridge 100 can be used to provide a sample and reagents to
the device 16. The fluidic cartridge 100 includes a housing 111
that protects various fluidic components such as reservoirs,
fluidic connections, pumps, valves and the like. A flow cell 112 is
integrated into the fluidic cartridge in a position where it is in
fluid communication with reagents within the housing. The housing
111 has an opening 113 through which a face of the flow cell 112 is
exposed such that it can interact optically with the optical
scanning device when the fluidic cartridge 100 is placed in the
cartridge receptacle 104. The cartridge housing 111 also includes a
sample port 114 for introduction of a target nucleic acid sample. A
bar code 115 or other machine readable indicia can optionally be
present on the cartridge housing 111, for example, to provide assay
capability tracking and management. Other indicia 116 can also be
present on the housing for convenient identification by a human
user, for example, to identify the manufacturer, analytical
analysis supported by the fluidic cartridge, lot number, expiration
date, safety warnings and the like. The apparatus shown in FIG. 3
is exemplary.
In some embodiments, the cartridge 100 may include additional
features, such as the light source (e.g., LEDs) that are configured
to provide excitation light to the reactions sites of the
biosensor. The cartridge 100 may also include a fluidic storage
system (e.g., storage for reagents, sample, and buffer) and a
fluidic control system (e.g., pumps, valves, and the like) for
fluidically transporting reaction components, sample, and the like
to the reaction sites. For example, after the biosensor component
of the cartridge is prepared or manufactured, the biosensor may be
coupled to a housing or container of the cartridge. In some
embodiments, the cartridges 100 may be self-contained, disposable
units. However, other embodiments may include an assembly with
removable parts that allow a user to access an interior of the
cartridge 100 for maintenance or replacement of components or
samples. The cartridge 100 may be removably coupled or engaged to
larger bioassay systems, such as a sequencing system, that conducts
controlled reactions therein.
FIG. 4 is a process flow diagram illustrating a method of
sequencing schedule management in accordance with some embodiments.
The method is generally indicated by reference number 150 and
includes various steps or actions represented by blocks. It should
be noted that the method 150 may be performed as an automated
procedure by a system, such as system 10. Further, certain steps or
portions of the method may be performed by a single device (e.g., a
controller 12) or by separate devices (e.g. a controller 12 and a
sequencing device 16). In embodiments, the method 150 may be
performed periodically as new information or samples enter the
system 10 or as samples exit the system 10.
According to the exemplary embodiment illustrated, the method 150
begins with the steps of receiving sequencing device information at
block 152 and receiving sample information at block 154. The
sequencing device information may include one or more of:
identification information (e g, manufacturer, model number) for a
sequencing device 16, assay capability information, information
about samples that have been loaded into a particular sequencing
device 16, estimated availability of a sequencing device 16, and
sequencing data. In certain embodiments, certain information about
the sequencing devices 16 (e.g., assay capability information) may
be stored on the controller 12 and looked up in response to
receiving identification information from a particular device 16.
For sequencing devices 16 that incorporate a cartridge 100, block
152 may also include information about the assay capabilities of
any inserted cartridge 100. The sample information may include
identification information (e.g., patient information), sample
type, preparation information, desired assay types, and a priority
designation (e.g., high priority, default or medium priority, low
priority). The method 150 assigns the sample to a sequencing device
16 based on a best match between the sequencing device information
and the sample information at block 158.
The controller 12 may use any appropriate algorithm or technique
for matching a sample to a sequencing device 16 based on the
available criteria. Such algorithms may implement Bayesian
optimization algorithms, heuristic approaches, colony optimization
algorithms, genetic algorithms, Monte Carlo modeling, and/or
weighted approaches. Matching solutions may be optimized with a
goal that any particular sequencing device 16 is operating on a
continuous flow basis. Other constraints may include null solutions
when the assay capabilities of a sequencing device 16 do not match
the desired assays for the sample.
At block 159, the method 150 provides an indication that the sample
is ready to be sequenced and/or is assigned to a particular
sequencing device 16. The indication may be in the form of a
generated schedule that may be viewed by an operator. Further, the
indication may be a text-based indication or an alarm. In other
embodiments, the indication may be an output sent to an automatic
sample loading system.
The techniques may also be applied to more complex systems that
include multiple sequencing devices and multiples samples. FIG. 5
is a flow diagram of a method 160 that includes the steps of
receiving sequencing device information from a plurality of
sequencing devices at block 162 and receiving sample information
from a plurality of samples at block 164. The method 160 determines
the availability of each sequencing device at block 166. The
availability may be based on a signal from a particular sequencing
device 16 or, in particular embodiments a lack of a signal. That
is, an unavailable sequencing device 16 may send a signal while a
sequencing run is in progress. The lack of any such signal may be
an indication that the device 16 is available. In other
embodiments, the sequencing device may send an estimated
availability time based on an estimated time of completion of an
ongoing sequencing run. The method 160 also determines a sequencing
schedule based on sample information, such as a desired assay type,
at block 168. At block 170, the method 160 compares the desired
assay type for each sample to the sequencing capabilities of the
sequencing devices 16. Finally, the method 160 generates a
sequencing schedule for the samples based on the availability, the
desired assay type, and any priority designation for the samples
based on the scheduling instructions, including weighting for
particular factors, at block 172.
In a particular embodiment, the system 10 may provide override
instructions for a case in which no sequencing devices 16 are
available for a high priority sample, as illustrated in FIG. 6. The
method 180 begins with the system 10 receiving information about an
ongoing run from an unavailable sequencing device at block 182. The
method 180 further receives information about the sequencing data
generated by the sequencing device 16 at block 184 and an estimated
time of completion at block 186. In one embodiment, the sequencing
device 16 generates nucleotide identity files on a rolling basis as
the run progresses. Genome assembly based on the nucleotide
identity files may be completed even before the sequencing run is
complete if sufficient information has been collected. That is,
genome sequencing may generate a certain percentage of redundant
sequencing data. However, a genome may be assembled from an
incomplete set of nucleotide identity files if sufficient data has
been collected. In particular embodiments, the sequencing device 16
may perform the assessment of whether sufficient data has been
collected for the assay in question. In other embodiments, the
nucleotide identity files may be sent to the controller 12, and the
controller 12 may perform the assessment. The assessment may be
based on an attempt to assemble at least a portion of the genome
from a minimum file set. In other embodiments, the assessment may
be based on empirical observation of a minimum run time or
percentage completion of a run to achieve a sufficient data set.
For example, the system 10 may include a look up table of a
percentage of minimum completion for types of organisms and
particular assays. In such a case, i.e., if sufficient data has
been collected to achieve a desired assay result, if the sample is
high priority (block 190), the sample may be assigned to the
sequencing device 16 that is in use (e.g., theoretically not
available) at block 192 and the method 180 provides an indication
that the ongoing run should be interrupted at block 194 so that the
higher priority sample can be loaded into the device 16. Otherwise,
for lower priority samples in the queue, even if the collected data
set is sufficient or represents a minimum required set, the
sequencing run is permitted to run to completion and the method 180
returns to block 182. That is, sequencing runs may be interrupted
only for high priority samples and, in particular embodiments, only
if sufficient data has been collected from the run.
In another embodiment, the override instructions may provide
instructions to load a high priority sample alongside the sample of
an ongoing run, as illustrated in FIG. 7. The method 200 beings
with the system 10 receiving information about an ongoing run from
an unavailable sequencing device at block 202. The method 200
further receives information about a sample density of the sample
being sequenced at block 204. If the ongoing samples is applied at
low density (block 206), the device may be available for high
priority samples (block 208). If both conditions are true, the
sample is assigned to the device 16 at block 210 and an indication
is provided that the sample should be applied alongside the sample
being sequenced. Depending on the characteristics of the ongoing
sample and the high priority sample, the high priority sample may
be tagged to distinguish the sample from the ongoing run. Further,
the samples may be related (e.g., from the same organism or
individual) or unrelated (e.g., different organisms or
individuals). For example tagging may occur via the Multiplexing
Sample Preparation Oligonucleotide Kit (Illumina) Such an
embodiment may take advantage of a sequencing run that is plated at
low density, which may occur if a control library is being
sequenced or for low diversity samples (e.g., expression studies
with an overrepresentation of one type of transcript, amplicon
pools, adapter dimer, and initial cycle indexing). In one
embodiment, a high throughput lab may keep one device 16 with
samples plated at low density at all times to serve as an overflow
machine for incoming high priority samples.
In another embodiment, the system 10 may schedule runs of a certain
type together. For example, for a scheduled whole genome or a whole
chromosome sequencing run, a device 16 may hold the run until
enough samples are loaded. In one embodiment, the samples may
represent different individuals.
Other scheduling considerations for the controller 12 may include
load balancing. FIG. 8 is a flow diagram of a method 220 for
shifting processing loads based on a total processing burden of the
system 10. After a sequencing schedule has been generated according
to the techniques described herein (block 222), a total processing
load may be estimated that follows the sequencing schedule (block
224). The processing load per sequencing device 16 may be estimated
based on a variety of factors, including manufacturer
specifications, sample type, assay type, duration of sequencing
run, and/or density of plating. The processing load of the entire
system 10 is based on the combined processing load of the
individual sequencing devices 16 within the system 10 and may vary
as the use of each sequencing device 16 changes over time according
to the generated sequencing schedule. Because high processing loads
may be costly, it may be advantageous to distribute the processing
load between local sequencing devices 16 and a cloud computing
environment if the processing load exceeds a certain threshold. In
one embodiment, the system 10 provides instructions to sequencing
devices 16 that are in communication with the cloud to perform data
analysis in the cloud (block 226), thus reducing the local
processing load. Such instructions may be provided automatically
upon generation of the sequencing schedule and a determination that
the estimated processing load exceeds a desirable threshold for a
particular time period.
In particular embodiments, the processing load, including any
availability of cloud-based processing resources, may be a factor
used in determining the sequencing schedule. For example, the
sequencing schedule may be optimized to smooth the processing load
over time. In other embodiment, the sequencing schedule may be
optimized to shift higher processing loads to times when processing
power may be cheaper (e.g., at night).
As described herein, the system 10 generates a sequencing schedule
to accommodate a queue of biological samples. The sequencing
schedule reduces operator decision making and optimizes efficient
use of resources. In particular embodiments of the disclosure, one
or more sequencing devices 16 may also be used in conjunction with
an automatic sample distribution system 300, as illustrated
diagrammatically in FIG. 9. The sample distribution system 300 may
be used either as a standalone system or in conjunction with the
sequence scheduling system 10. Further, while certain embodiments
may depict sample loading implementations, the disclosed techniques
may also be used to load samples and/or assay cartridges. That is,
the loading may be implemented on a per-cartridge basis. The sample
distribution system 300 includes a sample holder or rack 302 with
individual sample slots 304. Each sample slot 304 is in fluid
communication with respective conduits 306. As used herein, the
term "fluid communication" or "fluidically coupled" refers to two
spatial regions being connected together such that a liquid or gas
may flow between the two spatial regions. The terms "in fluid
communication" or "fluidically coupled" allow for two spatial
regions being in fluid communication through one or more valves,
restrictors, or other fluidic components that are configured to
control or regulate a flow of fluid through the system 300. The
system 300 may include one or more pumps or pneumatic devices to
pull fluid through the system in the direction of the sequencing
device 16.
The respective conduits 306 are coupled to a fluid junction 308
that includes a valve or other one-way control. The fluid junction
308 allows the fluid from only one of the conduits 306 to enter an
inlet path 310 at a particular time. The inlet path 310 is in fluid
communication with a sample loading port of the sequencing device
16. Accordingly, when the fluid junction 308 is coupled to a
specific conduit 306, the sample from a single sample slot 304 is
allowed to enter the inlet path 310. The fluid junction 308 may be
coupled to a sample controller 311, which includes a processor 312,
a memory architecture 314 storing executable instructions 316. In
specific embodiments, the sample controller 311 may include
operator input/output controls 318 and a display 320. Accordingly,
an operator may specify that a sample is ready to be loaded into
the sequencing device and provide instructions to the fluid
junction 308 via the sample controller 311 to allow the sample to
enter the inlet path 310 and the sequencing device 16. In one
example, the sample controller 311 may be implemented together with
the scheduling controller 12 (see FIG. 1) to provide automatic
distribution of scheduled samples to assigned devices.
In one embodiment of the present techniques, multiple samples may
be queued in the inlet path 310. For example, the fluid junction
may permit entry of the sample from one conduit 306, then close
that pathway and allow entry of a second sample. The pathway may be
cleaned between samples via a cleaning fluid reservoir 324. The
sample controller 311 may control access of the cleaning fluid to
the inlet path 310. In one example, a sample queue in the inlet
path 310 may be separated by a cleaning fluid, such as a detergent,
oil, or a combination thereof.
As illustrated, the sequencing device 16 may include one or more
cartridges, such as a sample preparation cartridge 320 and a
sequencing data acquisition cartridge 322. The sample enters the
sample preparation cartridge 320, is prepared according to the
specific configuration and reagents available in the cartridge 320,
and enters the sequencing data acquisition cartridge 322 to be, for
example, plated and imaged during cluster generation in a
particular embodiment. In the depicted embodiment, the sample may
be applied to the sample slot without being prepared for a
particular assay. In other embodiments, the sample preparation may
occur being the sample enters the system 300. Further, the
sequencing device may not include any sample preparation cartridge
320. However, providing a sample preparation cartridge 320 housed
within the sequencing device 16 may allow a particular sample to be
separated to undergo multiple assays in parallel.
For example, the sample distribution system 300 may be used in
conjunction with multiple sequencing devices 16 and to apply
multiple samples to the devices 20. FIG. 10 is a diagrammatic view
of a rack configuration having a cabinet or carriage 340 with a
plurality of sequencing devices loaded thereon. The cabinet 340 may
include one or more shelves 342 that define one or more reception
spaces 344 configured to receive the sequencing devices 16.
Although not shown, the sequencing devices 16 may be
communicatively coupled to a communication network that permits a
user to control operation of the sequencing devices 16. The
sequencing devices 16 may also be coupled to the system 10 for
sample scheduling.
Further, it is envisioned that the sample distribution system 300
may be interoperable with various types of sequencing devices. To
that end, the sample distribution system may be implemented as a
fluidic backplane that is sized and shaped to plug onto the sample
insertion side of the sequencing devices 16. FIG. 11 shows an
example of one implementation of backplane 350 that includes a
housing 352 and a coupler 354 for the inlet path 310. The coupler
354 is designed to plug into a sample loading port of a sequencing
device 16. A sample distribution system 300 may include one or more
backplanes 350. In one embodiment, the backplane 350 may be sized
and shaped to form a side of a cabinet 340 (see FIG. 10). That is,
the backplane 350 may be coupled to the cabinet 340 and the
sequencing devices 16 interface with the backplane while positioned
in the cabinet 340. The backplane 350 may include one or more
electrical connectors and identification features. For example, the
backplane 350 may include a USB connector configured to mate to a
USB port on the sequencing device 16.
While only certain features of the invention have been illustrated
and described herein, many modifications and changes will occur to
those skilled in the art. It is, therefore, to be understood that
the appended claims are intended to cover all such modifications
and changes as fall within the true spirit of the invention.
* * * * *
References